Mesenchymal stem cells from umbilical cord tissue as potential therapeutics for cardiomyodegenerative diseases - a review.

Heart failure is one of the leading causes of death worldwide. End stage disease often requires heart transplantation, which is hampered by donor organ shortage. Tissue engineering represents a promising alternative approach for cardiac repair. For the generation of artificial heart muscle tissue several cell types, scaffold materials and bioreactor designs are under investigation. In this review, the use of mesenchymal stem cells derived from human umbilical cord tissue (UCMSC) for cardiac tissue engineering will be discussed.

n humans, the heart is one of the least regenerative organs in the body (1). The limited ability of the heart to regenerate damaged tissue after major cardiac injuries often leads to heart failure (2). Despite a wide range of therapeutic approaches, heart failure remains the leading cause of death in modern societies (3,4). Myocardial infarction is the major cause of heart failure.
Ischemic conditions result in an irreversible loss of functional cardiomyocytes which are gradually replaced by fibroblasts, forming non-contractile scar tissue (5). Resident cardiac progenitor cells can be found in transplanted human hearts, and evidence of myocyte proliferation in the human heart exists. However, this proliferation does not compensate for up to 1 billion cardiomyocytes being lost after MI (6). In end stage heart failure allogeneic heart transplantation remains the last treatment option, but it is limited due to donor organ shortage. According to the Eurotransplant International Foundation, in 2011 the demand for donor hearts was covered only to 35 % in Germany (7). The generation of artificial heart muscle tissue using cardiac tissue engineering might be a reasonable alternative to heart transplantation.

Cardiac tissue engineering
Cardiac tissue engineering is an interdisciplinary research area in regenerative medicine. Besides paracrine effects supporting angiogenesis, modulation of extracellular matrix components, and stimulating interactions with resident cardiac progenitor cells, the main aim of I tissue engineering is the repopulation of the diseased myocardium with cells that can restore contractility (8)(9)(10)(11).

Cell application
The route of administration of autologous and allogeneic cells is one of the central questions in cardiac tissue engineering. Cellular cardiomyoplasty is performed by intracoronary injection or direct implantation of a single cell suspension into the myocardium (12). Animal studies demonstrate an increase in the pumping function of the heart. However, myocardial regeneration was not observed (13). Functional improvement could be explained by secretion and stimulation of angiogenic growth factors resulting in the lack of myogenesis stimulation and contractility improvement (14). Systemic application also carries the risk of pulmonary accumulation of cells.
Experimental injection of cells into the infarcted region ensures the delivery to the damaged area but is hampered by significant cell loss (12,15).
An alternative approach to injection of isolated cells into the heart is the use of artificially  (17).
For myocardiac regeneration, cells from several cell sources like skeletal muscle (18) or neonatal rat heart (19) have been investigated already. Although some of these cell types integrate into damaged myocardium, application is restricted by limited availability and poor proliferation capacity (20).
This has led to the search for alternative more efficient cell populations.

Cell sources
Heart muscle regeneration requires cells with the capability for proliferation, plasticity and functional integration into cardiac tissue (21). Stem cells feature unique regenerative potential and are consequently qualified for this claim (22)(23)(24)  mesenchymal origin, nerve and myogenic cells.
Besides a comparable differentiation capacity, MSC seem to be more efficacious in tissue reconstitution than adult hematopoetic stem cells, due to strong pro-angiogenic properties necessary for a functional myocardium (33).
Moreover, MSC show a higher homing potential towards tissue defects resulting in the production of repairing growth factors (34,35).
Since they have the ability to differentiate into cardiomyocyte (36), MSC are a potential cellular source for cardiac stem cell-based therapy (35,37).
MSC have been already tested clinically and do not raise any ethical concerns (38

Cardiomyogenic differentiation
Cardiomyogenic differentiation is However, our study showed that UCMSC  To overcome the limitation of biological coatings, a hydrophilic titanium-coated surface can

Bioreactors
For the use of tissue engineered constructs in vivo, it is essential to examine their functionality and mechanical integrity prior to implantation (107 (110)(111)(112).
In heart valve fabrication, bioreactors for tissue formation under dynamic culture conditions were demonstrated several times (107,113,114).
Bioreactors also support tissue formation of heart muscle in vitro (115,116). An effective approach to